Table 4.
Risk loci identified in cross-ancestry genome-wide association study (GWAS), the associated function and disease mechanism in Parkinson’s disease.
| S.No. | Gene (PD) | Function | Mechanism |
|---|---|---|---|
| 1 | KRTCAP2 | Dementia-related gene | Inflammation and neurodegeneration [260] |
| 2 | PMVK | Involved in mevalonate pathway | Not clear. Possibly same as GBA [261] |
| 3 | GBAP1 | Encodes for the enzyme glucocerebrosidase (GCase), a lysosomal enzyme | Lysosomal dysfunction [262] |
| 4 | FCGR2A | Phagocytosis and modulates inflammatory responses | Binds with IgG-specific immune complexes and activates signaling [263] |
| 5 | VAMP4 | Endosomal trafficking of synaptic proteins | Impaired synaptic signaling and lysosomal degradation [264] |
| 6 | NUCKS1 | Cell growth and proliferation [265] | Not clear |
| 7 | RAB29 | Lysosome-related organelle biogenesis | Lysosomal dysfunction Axon termination [266] |
| 8 | ITPKB | Involved in inositol metabolism and calcium release from ER | Causes α-synuclein aggregation by dysregulated calcium release from ER-to-mitochondria [267] |
| 9 | SIPA1L2 | Controls protein trafficking and BDNF/TrkB signaling [268] | Not clear; possibly abrupt synaptic signaling |
| 10 | KCNS3 | Potassium channel | Neuroinflammation [269] |
| 11 | KCNIP3 | Associated with inositol biosynthetic pathway [270] | Not clear |
| 12 | MAP4K4 | Cell proliferation, inflammation, and stress response | Cytokine activation and neuroinflammation [271] |
| 13 | TMEM163 | Influx or efflux transporter particularly Zn transport [272] | Not clear |
| 14 | STK39 | Immune regulation | Inflammatory pathway [273] |
| 15 | SATB1 | Transcriptional response in dopaminergic neurons | Senescence-mediated neuroinflammation [274] |
| 16 | LINC00693 | Involved in miRNA processing complex [275] | Might affect protein expression and accumulation |
| 17 | IP6K2 | Mitochondrial respiration | Mitophagy via PINK1 signaling [276] |
| 18 | KPNA1 | Encodes importin α5 and is involved in lysosomal biogenesis and autophagy | Disturbed protein degradation [277] |
| 19 | MED12L | Transcriptional coactivation of nearly all RNA polymerase II-dependent genes, Wnt/beta-catenin pathway, and immune response [278] | Possibly transcriptional defects |
| 20 | SPTSSB | Regulates de novo synthesis of ceramides | Neuronal signaling, synaptic transmission, cell metabolism [279] |
| 21 | MCCC1 | Mitochondrial enzyme and involved in leucine catabolism [280] | Possibly associated with mitochondrial dysfunction |
| 22 | GAK | Associated with lysosomal and chaperons | Defected lysosomal-mediated protein degradation [281] |
| 23 | TMEM175 | Proton channel to maintain optimum pH in lysosomes | Downregulation of TMEM175 causes lysosomal over-acidification, impaired proteolytic activity, and facilitated a-synuclein aggregation [282] |
| 24 | BST1 | Serves as a receptor that regulates leukocyte adhesion and migration | Immune regulation and inflammation [283] |
| 25 | LCORL | - | - |
| 26 | SCARB2 | Encodes a receptor responsible for the transport of glucocerebrosidase (GCase) to the lysosome | Associated with lysosomal defects [284] |
| 27 | FAM47E | Present in close proximity to SCARB2 | Lysosome/autophagy dysfunction |
| 28 | FAM47E-STBD1 | - | - |
| 29 | SNCA | Dopamine release and transport, fibrillization of MAPT, and suppression of both p53 expression and transactivation of proapoptotic genes leading to decreased caspase-3 activation | Synuclein aggregation and induction of apoptosis [285] |
| 30 | CAMK2D | Calcium/calmodulin-dependent protein kinase ii delta. Involved in synaptic plasticity |
Disturbed calcium signaling and synaptic function [286] |
| 31 | CLCN3 | Ion channel transporter and neurotransmitter signaling [239]. | Disturbed synaptic signaling |
| 32 | ELOVL7 | Catalyzing the elongation of very long-chain fatty acids. | Possibly disturbed lipid metabolism and oxidative stress [287] |
| 33 | PAM | Glutamate receptor at parasynapses, associated with anxiety and hyperexcitation. | Disturbed glutamatergic and GABA signaling [288] |
| 34 | C5orf24 | - | Function and mechanism are not clear. However, upregulated expression and DNA methylation in disease condition [289] |
| 35 | LOC100131289 | - | - |
| 36 | TRIM40 | E3 ubiquitin-protein ligase and inhibits NF-κB activity | Protein degradation and inflammation [290] |
| 37 | HLA-DRB5 | Immune regulation | Inflammation [291] |
| 38 | RIMS1 | Encodes a synaptic protein and involved in neurotransmitter release and synaptic transmission [277] | Possibly perturbance in synaptic signaling |
| 39 | FYN | Ion channel function, growth factor receptor signaling, immune system regulation. | Activates BDNF/TrkB, PKCδ, NF-κB, MAPK, Nrf2, and NMDAR signaling pathway and induces synuclein phosphorylation, inflammation and excitotoxicity [292] |
| 40 | RPS12 | A special function in cell competition that defines the competitiveness of cells. | Not clear in PD; however, reported to cause inflammation [293] |
| 41 | GPNMB | Cell differentiation, migration, proliferation | Interacts with a-synuclein and induces its phosphorylation, cellular internalization, and fibrillization [294] |
| 42 | GS1-124K5.11 | - | - |
| 43 | CTSB | Lysosomal hydrolase cathepsin B involved in waste degradation in cells | Autophagy and lysosomal dysfunction causing a-synuclein aggregation [295] |
| 44 | FGF20 | Maintenance of dopaminergic neurons | Affects dopaminergic neurons in paracrine manner [296] |
| 45 | BIN3 | Cytokinesis and RNA methyltransferase | Probably target transcription and translation step [297] |
| 46 | FAM49B | Regulates mitochondrial function | Mitochondrial fission, oxidative stress, and inflammation [298] |
| 47 | SH3GL2 | Encodes Endophilin A which regulates autophagy in calcium dependent manner | Autophagy dysfunction at synapses [299] |
| 48 | UBAP2 | Synapse formation, maintenance, and signaling | - |
| 49 | ITGA8 | Alpha8 integrin, cell adhesion, cell signaling, and cytoskeletal organization | Increases cell-to-cell transfer of a-Syn [300] |
| 50 | GBF1 | Maintenance and function of the Golgi apparatus, and mitochondria migration and positioning | Increase in Golgi fragmentation [301] |
| 51 | BAG3 | A chaperone and regulates autophagy | Its downregulation promotes autophagy dysfunction and disease progression [302] |
| 52 | INPP5F | PI4P-phosphatase Involved in endocytic pathway |
Disturbed endocytosis [303] |
| 53 | RNF141 | - | - |
| 54 | DLG2 | DLG2-encoded protein involved in glutamate receptor phosphorylation | Phosphorylation of NR2 subunit and hyperexcitability [280] |
| 55 | IGSF9B | Cell adhesion molecule at inhibitory synapses and plays role in neuroplasticity and synaptic transmission | Any disturbance in inhibitory synapses causes dysregulation of information flow and cognitive defects [304] |
| 56 | LRRK2 | Associated with intracellular membranes and vesicular structures | Causes accumulation of a-synuclein, which activates MAPK signaling and microglial activation leading to inflammation [305] |
| 57 | SCAF11 | Encodes a caspase | - |
| 58 | HIP1R | Clathrin-mediated endocytosis, actin dynamics, intrinsic cell death pathway [306] | Not clear. Probably affects the endocytosis of a-synuclein and activate caspase response |
| 59 | FBRSL1 | - | - |
| 60 | CAB39L | Encodes calcium binding 39-like protein | - |
| 61 | MBNL2 | Encodes for the muscleblind-like protein 2, which belongs to a conserved family of RNA-binding proteins | Reduced MBNL2 expression accompanied by the reduction in a developmental RNA processing [307] |
| 62 | MIPOL1 | - | - |
| 63 | GCH1 | Essential for dopamine production | Affects dopaminergic signaling [308] |
| 64 | RPS6KL1 | - | - |
| 65 | GALC | Encodes galactocerebrosidase | Impaired autophagy and disturbed protein trafficking causes a-synuclein deposition [309] |
| 66 | VPS13C | Localized to the outer membrane of mitochondria | PINK1/Parkin-dependent mitophagy [310] |
| 67 | SYT17 | Encodes synaptotagmin-17, associated with vesicle trafficking and transport at synapses |
Disturbed synaptic trafficking [311] |
| 68 | CD19 | Immune regulatory molecule presents on B lymphocyte | Neuroinflammation by suppressing local immune response [312] |
| 69 | SETD1A | Histone methyltransferase | Might affect synaptic signaling, excitation and glutamatergic signaling [313] |
| 70 | NOD2 | Immune homeostasis | Nox-2-mediated oxidative stress and neuroinflammation followed by loss of dopaminergic neurons [314] |
| 71 | CASC16 | - | - |
| 72 | CHD9 | Activates transcription factor CREBPP, Involve in Notch signaling | Aberrant survival signaling pathway [315] |
| 73 | CHRNB1 | Encodes subunit of the n-acetylcholine receptor, Ion channels, transporters, and neurotransmitter signaling [239] | Disturbed cholinergic signaling |
| 74 | RETREG3 | Involved in ER autophagy | Activation of ER autophagy by mTOR signaling [316] |
| 75 | UBTF | Transcription factor associated with ds-DNA break and apoptosis | Altered protein expression [317] |
| 76 | BRIP1 | Facilitates repair of SSBs and DSBs | Excitotoxicity, mitochondrial damage, and cell death [318] |
| 77 | DNAH17 | Encodes dynein axonemal heavy chain 17 involved in cytokinesis, microtubule-based movement, mitotic spindle organization, meiotic nuclear division [319] | - |
| 78 | ASXL3 | - | - |
| 79 | RIT2 | Involved in lysosomal activity | Activate LRRK2 gene and lysosomal dysfunction and leads to a-synuclein deposition [320] |
| 80 | MEX3C | Encodes RNF 194, an RNA binding protein impart immunoregulatory role | Neuroinflammation [321] |
| 81 | SPPL2B | - | - |
| 82 | CRLS1 | Encodes cardiolipin synthase 1, involved in mitochondrial membrane formation | Mitophagy [322] |
| 83 | DYRK1A | Synaptic and nuclear proteins, including transcription factors | Causes phosphorylation of a-synuclein and downregulates PI3K/AKT pathway to induce apoptosis [323] |
| 84 | FAM171A2 | Downstream of GRN, is a novel genetic regulator of progranulin production expressed on microglial surface | Downregulates progranulin level in brain [324] |
| 85 | CRHR1 | Encodes corticotropin-releasing hormone receptor, involved in regulation of stress and immune responses | Downregulates CREB signaling [325] |
| 86 | WNT3 | Immune regulation | PD-related gene expression in immune cells [291] |